Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. There are two generally recognized forms of diabetes. In Type diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In Type II diabetes, or non-insulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects. However, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues. The plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance, resulting in hyperglycemia.
Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic diseases. For example, patients with Type II diabetes mellitus are at especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, and neuropathy.
Obesity and being overweight are generally defined by body mass index (BMI), which is correlated with total body fat and serves as a measure of the risk of certain diseases. BMI is calculated by weight in kilograms divided by height in meters squared (kg/m2). Overweight is typically defined as a BMI of 25-29.9 kg/m2, and obesity is typically defined as a BMI of 30 kg/m2 or higher. See, e.g., National Heart, Lung, and Blood Institute, Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults, The Evidence Report, Washington, D.C.: U.S. Department of Health and Human Services, NIH publication no. 98-4083 (1998).
Overweight or obese individuals are at increased risk for ailments such as hypertension, dyslipidemia, Type II (non-insulin dependent) diabetes, insulin resistance, glucose intolerance, hyperinsulinemia, coronary heart disease, angina pectoris, congestive heart failure, stroke, gallstones, cholescystitis, cholelithiasis, gout, osteoarthritis, obstructive sleep apnea and respiratory problems, gall bladder disease, certain forms of cancer (e.g. endometrial, breast, prostate, and colon) and psychological disorders (such as depression, eating disorders, distorted body image and low self esteem). The negative health consequences of obesity make it the second leading cause of preventable death in the United States and impart a significant economic and psychosocial effect on society. See, McGinnis M, Foege W H., “Actual Causes of Death in the United States,” JAMA 270:2207-12, 1993.
Obesity is now recognized as a chronic disease that requires treatment to reduce its associated health risks. Although weight loss is an important treatment outcome, one of the main goals of obesity management is to improve cardiovascular and metabolic values to reduce obesity-related morbidity and mortality. It has been shown that 5-10% loss of body weight can substantially improve metabolic values, such as blood glucose, blood pressure, and lipid concentrations. Hence, it is believed that a 5-10% reduction in body weight may reduce morbidity and mortality. Currently available prescription drugs for managing obesity generally reduce weight by decreasing dietary fat absorption, as with orlistat, or by creating an energy deficit by reducing food intake and/or increasing energy expenditure, as seen with sibutramine.
Current treatments for Type II diabetes include administration of exogenous insulin, oral administration of drugs and dietary therapies and exercise regimens. In 2005, exenatide (exendin-4; Byetta®) was FDA approved as an adjunct therapy for Type II diabetics who are taking metformin and/or a sulfonylurea but who have not achieved adequate glycemic control. Exenatide is exendin-4, a potent GLP-1 receptor agonist that is an endogenous product in the salivary glands of the Gila monster. Like GLP-1, exendin-4 is an incretin. It is insulinotropic, inhibits food intake and gastric emptying, and is trophic to β-cells in rodents (Parks et al., Metabolism. 50: 583-589, 2001; Aziz and Anderson, J. Nutr. 132: 990-995, 2002; and Egan et al., J. Clin. Endocrinol. Metab. 87: 1282-1290, 2002). Further, due to the presence of glycine at position 2 of its N-terminus, it is not a substrate for DPPIV, as is GLP-1. The downside to the use of exenatide is that it must be injected twice daily because its t1/2 is only 2-4 hours (Kolterman et al., J. Clin. Endocrinol. Metab. 88: 3082-3089, 2003 and Fineman et al., Diabetes Care. 26: 2370-2377, 2003).
Accordingly, a need remains for a longer-fasting, degradation resistant GLP-1 receptor agonist molecule that can be used as a therapeutic to provide glycemic control and to reduce body weight. Development of a long acting incretin mimetic offers the ability to enhance glycemic control through continuous enhancement of glucose-dependent insulin secretion, with the convenience of less frequent dosing. The present invention fulfills this need by providing exendin-4 molecules fused to a modified transferrin, which extends the in vivo circulatory half-life of the exendin-4 while maintaining bioactivity. Additionally, use of a fusion protein of the invention may reduce the high incidence of nausea and vomiting currently associated with use of incretins.